Objective: Traumatic Brain Injury (TBI) has been labeled the signature injury of the conflicts in Iraq and Afghanistan. Clinically, TBI patients are heterogeneous in their symptomatology because of variability in location and severity of injury. This lack of uniformity leads to many challenges in researching the disease process. While the brain injuries suffered by soldiers in the theater of combat operations are variable, several aspects of the environment are constant. Combat operations require high level of sustained arousal as well as prolonged periods of sleep deprivation. The impact of these factors on TBI has not been studied. This proposal seeks to investigate the impact of sleep deprivation on function as well as neuropathology following traumatic brain injury. Research Plan and Methodology: To better define the impact of sleep deprivation on a rat model of traumatic brain injury, 4 groups of rats will be studied. The groups will be randomized to one of the following conditions for 24 hours prior to surgery: REM sleep deprived, social isolation, normal rat laboratory environment. Baseline neurobehavioral testing will be completed in all rats. Three groups of 8 rats will undergo surgically induced TBI via the Closed Cortical Impact (CCI) model and a 4th group will have sham surgery following 24 hours of a normal laboratory environment. Following TBI, neurobehavioral testing will be repeated and following sacrifice, neuropathologic and histochemical testing will be completed to evaluate for evidence of differences in pathology, markers of inflammation, and apoptotic cell death. Clinical Significance: Most clinical studies of traumatic brain injury have been in populations where the environment is relatively constant and secure. Similarly, rat models of TBI involve a population of animals who are typically not physically or environmentally stressed prior to injury. Sleep deprivation models have created conditions which theoretically could be associated with increased pathologic injury following TBI. The study of TBI in rats that have been sleep deprived will allow the evaluation of the impact a prominent environmental variable in combat has on TBI. If there are obvious differences in the two populations, the study will be expanded to better define the biochemical mechanism of the difference as well as offer evidence to develop improved protection of soldiers in the combat zone. PUBLIC HEALTH RELEVANCE: Traumatic Brain Injury (TBI) has been labeled the signature injury of the conflicts in Iraq and Afghanistan. TBI, in the acute and chronic phase, impacts the physical and cognitive function of the individual. Subsequently, these individuals can have a difficult time returning to be productive members of their military unit or society. Clinically, TBI patients are heterogeneous in their symptoms because of variability in location and severity of injury. This lack of uniformity leads to many challenges in researching the disease process. However, numerous animal models of TBI exist that are able to produce relatively homogenous injuries. Thus, animal models allow for ease of studying the pathology and molecular mechanisms of TBI. While the brain injuries suffered by soldiers in the theater of combat operations are variable, several aspects of the environment are constant. Combat operations require a high level of sustained arousal as well as prolonged periods of sleep deprivation. The impact of these factors on TBI has not been studied. Sleep deprivation has known effects on nervous system function as well as its neurophysiologic and neurochemical underpinnings. This proposal seeks to investigate the impact of sleep deprivation with sustained arousal on behavior as well as neuropathology following traumatic brain injury. The study of TBI in rats that have been sleep deprived will allow the evaluation of the impact a prominent environmental variable in combat has on TBI. If there are obvious differences in the two populations, the study could be expanded to better define the biochemical mechanism of the difference, offer evidence to develop improved protection of soldiers in the combat zone, and alter the treatment paradigms employed for both soldiers and veterans.